Research into new therapeutic strategies for treating pediatric solid tumors is focused on bone and soft-tissue sarcomas (Ewing's sarcoma, peripheral neuroepithelioma, rhabdomyosarcoma, osteosarcoma, neuroblastoma, and malignant brain tumors), which remain diagnostic and therapeutic challenges for which new approaches are needed. These tumors are an excellent model system for exploring strategies and hypotheses with broad applicability to both pediatric and adult solid tumor oncology. The goal of these protocols is to learn how to optimize the use of the known active agents and to identify active new agents and therapeutic strategies. Previous Pediatric Branch protocols demonstrated a very high response rate for intensive vincristine, adriamycin and cyclophosphamide (VAdrC) in newly diagnosed sarcoma pts (83-C-73) and a high level of activity for ifosfamide, mesna and etoposide (IE) in those with recurrent tumors (85-C-154). Our recently completed front-line sarcoma protocol (86- C-169) evaluated the feasibility of integrating the IE combination with intensive VAdrC, with radiation therapy for local control. This regimen maintained the high initial response rate of the 83-C-73 regimen. but did not translate into an improved outcome for pts with metastatic tumors, and it is too soon to tell if there will be any improvement in outcome for those with localized disease. To circumvent the major toxicities associated with this protocol, we conducted two companion, randomized trials: one, of rh-GM-CSF (88-C-165) to determine whether its use could decrease myelosuppression and its related delays and complications; the second, of the iron chelator ICRF-187 (89-C-07) to assess if it could prevent adriamycin induced myocardial damage. These studies were the only front-line trials of these promising new approaches in pediatric solid tumor pts. and have now been completed. ICRF-187 was found to be cardioprotective, with no evidence of tumor protection or additive toxicity. GM-CSF was found to have some benefit on reducing myeloid toxicity, but was associated with greater platelet toxicity. Our new front-line sarcoma study will assess the activity of new agents against the pediatric solid tumors in a phase II "window" design, as well as pilot the use of peripheral blood progenitor cells as a means of permitting increased dose intensity.